Abstract: Concerns over a Zika virus outbreak are in the news every day and for good reason: a simple mosquito bite can result in viral infection that can not only cause debilitating birth defects (e.g., microcephaly), but can also substantially increase the risk for Guillain-Barre syndrome (GBS), a seriously debilitating and sometimes lethal autoimmune neurological disorder. Acute phase GBS most often results in a flaccid paralysis requiring critical care for an average of four weeks. While two-thirds of GBS patients will achieve a full recovery, this takes months to years to achieve. Even more troubling is that a number of additional mosquito-borne infectious outbreaks, including Dengue and Chikungunya and others, have been recently linked to increased incidents of GBS. While mechanical ventilation may lower the risk of mortality and plasma exchange or intravenous immunoglobulin therapy may speed recovery from the acute phase, there are no approved treatments for GBS. Thus, in the case of Zika-, Dengue- or Chikungunya-induced GBS there is no better treatment than prevention, and prevention is guaranteed if mosquito bites can be avoided. Mosquito-borne illnesses, such as Zika, Dengue, Chikungunya and others, are a costly and growing public health risk in the United States and its territories. The elderly are disproportionately impacted by mosquito-borne illness being much more likely to progress to the neuroinvasive forms and to die. Prevention of biting by mosquitoes stops disease transmission, but there are concerns that mosquitoes are becoming increasingly resistant and tolerant to DEET, the predominant active ingredient in topically-applied commercial insect repellents. Potential DEET alternatives, like picaridin, IR3535 and others, all share common receptor targets and thus DEET tolerant insects are likely to be insensitive or tolerant to these alternatives as well. In light of these issues, we are seeking to develop novel synthetic mosquito deterrents that exploit a different mode of action and that safely protect against biting by the two major genera of disease- carrying mosquitoes, Aedes and Anopheles. In order to achieve this goal, we are proposing to create the biological tools and develop methodologies necessary to correlate the chemical structures of novel repellent molecules with mosquito octopamine receptor agonist properties, protection against mosquito biting, and low potential for dermal irritancy, skin penetration, and toxicity. The results obtained will help advance towards our ultimate translational goal of developing a new chemical class of safe topical agents that prevent disease transmission by protecting against mosquito bites.